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Flashcards in pharmacogenics Deck (101)
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1

pharmacodynamics

what the drug does to the body

mechanism of effect (action)
sensitivity
responsiveness

2

pharmacokinetics

what the body does to the drug

absorption
distribution
metabolism
excretion

3

central compartment blood and body mass

75% of blood flow, 10% body mass

4

a tissue that accumulates a drug preferentially may

act as a reservoir to maintain the plasma concentration and thus prolong its duration of action

5

Rate of transfer between central and peripheral compartments decreases

with aging !

6

pKa =

the pH at which 50% of a drug will be in its ionized form.

7

Blood brain barrier works by

the limited permeability characteristics of the brain capillaries

8

the only limitation to permeation of the CNS by lipid soluble, non-ionized drugs is

cerebral blood flow

9

Blood brain barrier can be overcome by

administration of large doses

or be disrupted by acute head injury or arterial hypoxemia

10

effect site equilibration time

time it takes from administration of an IV drug to effect of drug

11

Ke0

rate constant of ELIMINATION from EFFECT SITE

12

Vd formula

dose of IV drug / plasma concentration before any has been eliminated

13

volume of distribution is influenced by

1. lipid solubility
2. protein binding
3. molecular size

14

A drug that is not very lipid soluble and highly protein bound

Will not be able to cross membranes (not lipid soluble), will be bound to plasma protein (high protein binding) and therefore will remain mostly in the PLASMA.

So it will have a SMALLER Vd.

15

A lipid-soluble drug that is highly concentrated in tissues with a resulting low plasma concentration

will have a calculated Vd that exceeds total body water

16

Elimination Half Time

the time it takes for the PLASMA CONCENTRATION of a drug to decline 50% during elimination phase

17

Elimination half time is directly proportional to

volume of distribution

18

elimination half time is independent of

dose of drug administered

19

Elimination half time is inversely proportional to

clearance of drug

20

Near total (96.9%) elimination of drug from body requires

5 elimination half times

21

Elimination half life

time it takes to eliminate 50% of drug from BODY after its IV injection

22

Context Sensitive Half Time

time it takes for 50% decrease in plasma concentration of drug AFTER DISCONTINUATION OF IV INFUSION

23

Context sensitive half time depends on

Distribution AND excretion
physiochemical properties of the drug AND length of infusion

24

Context sensitive halftime relates to elimination half time

Context sensitive half time bears no constant relationship to the drugs elimination half-time

25

System absorption depends on

System absorption, regardless of route, depends on the drugs solubility

26

Disadvantages of oral administration

emesis, destruction by enzymes or acidic gastric fluid, irregular absorption with food or other drugs.

27

Principle site of drug absorption after PO administration is

small intestine r/t large surface area

28

changes in pH of GI fluid that favor the presence of a drug in its non-ionized form

favor systemic absorption

(lipid-soluble)

29

First Pass Hepatic Effect happens because

Drugs absorbed in the GI system first enter the portal venous blood and pass through the liver BEFORE entering the systemic circulation [[for delivery to tissue receptors]]

drugs in the liver are extensively metabolized.

30

reason for large differences between bioavailability of PO and IV drugs is

first pass hepatic effect

31

Sublingual/transmucosal administration is characterized by

rapid onset, bypasses the liver so no first pass hepatic effect.

32

Transdermal administration characteristics

provides sustained therapeutic plasma []

absorption occurs along sweat ducts and hair follicles that function as diffusion shunts

33

Things that affect the skin's permeability to drugs

thickness and blood flow

why scopolamine goes behind the ear and not on your hand

34

Rectal administration, proximal vs distal

proximal rectal administration is absorbed by superior hemorrhoid veins to portal vein so FIRST PASS EFFECT.

Distal rectal administration bypasses the portal system

Difference is why drug administration via rectum is unpredictable.

35

Most drugs are present in both

ionized and non-ionized forms.

Because most drugs are WEAK ACIDS OR BASES.

36

ionized fraction of drugs are excreted

by the kidneys unchanged.

37

Degree of ionization depends on

the drugs dissociation constant pK and the surrounding pH

38

Changes in pH can affect

the degree to which a drug ionizes

39

When the pK = pH

50% of the drug is in its ionized form and 50% of the drug is non-ionized (lipid-soluble)

40

Ion trapping

ex. when a (basic) drug as lipid-soluble version crosses a membrane to a different environment (more acidic) and then ionizes.

Now ionized form is trapped on one side o membrane and also causes a concentration gradient for more of the drug to cross the membrane.

ex. placenta

41

Protein binding is inversely proportional to

Volume of distribution

42

Unbound drugs in the plasma are more

easily metabolized and excreted

43

Protein binding of drugs facilitates

elimination,

44

Alterations in protein binding are more important for drugs that are

Highly protein bound (94 vs 96 compared to 70 vs 68)

45

Low plasma concentration of drugs aren like to be more

highly protein bound than are higher plasma concentrations of the same drug

46

Renal failure may decrease

the fraction of a drug bound to protein even in the absence of changes in plasma concentrations of albumin or other proteins.

--> something the kidneys usually excrete competes for binding sites on albumin

47

clearance is defined as

volume of plasma cleared of drug by metabolism and excretion

volume of plasma cleared of drug per unit time

48

almost all drugs administered in therapeutic dose range are cleared by

first order kinetics

(at a rate proportional to the amount of drug present in the plasma)

49

Non organ clearance mechanisms

Hofmann Elimination and ester hydrolysis. Both happen in plasma

50

Zero order kinetics

a constant amount of drug is cleared per unit of time.

when drugs exceed the metabolic or excretory capacity of the body to clear drugs by first order kinetics.

51

Hepatic clearance is dependent on

blood and extraction ratio

52

Hepatic extraction ratio >0.7

Perfusion-dependent elimination

increased blood flow = increased clearance
clearance will depend on hepatic blood flow.

53

Hepatic extraction ratio <0.3

Capacity dependent elimination

A decrease in protein binding or an increase in enzyme activity will increase hepatic clearance.

54

Most important organ for elimination of unchanged durgs

kidneys

55

Highly lipid soluble drugs in the kidneys

Are reabsorbed

56

Increased water solubility for a drug and Vd

Increased water solubility of drug DECREASES vd and would enhance its renal excretion

57

zero order kinetics occurs when

the plasma concentration of a drug exceeds the capacity of metabolizing enzymes.

Reflects saturation of available enzymes and results in metabolism at a constant amount of drug per unit of time.

58

Constant amount of drug metabolized per unit of time in zero order kinetics is dependent on

intrinsic activity of enzymes

59

Four Basic Pathways of Metabolism

Oxidation, Reduction, Hydrolysis, Conjugation

60

Phase I reactions of metabolism

Oxidation, reduction, hydrolysis

increase the drug's POLARITY,

61

Phase II reactions of metabolism

conjugation.

covalently link drug with highly polar molecule to make it water soluble enough for excretion

62

Hepatic microsomal enzymes are involved in

oxidation, reduction, and conjugation

63

CYP isozymes (6)

CYP1A2
CYP2C9
CYP2C19
CYP2D6
CYP2E1
CYP3A1

64

non-microsomal enzymes metabolize drugs mostly by

hydrolysis and conjugation

lesser degree oxidation, reduction

65

receptor occupancy theory

the more receptors occupied by a drug the more effect

66

non-receptor drug action

chelating drugs form bonds with metallic cations that may be found in body

67

Agonist drugs

bind to sites and mimic cell signaling molecules , these cause similar effects at receptors

68

Antagonist drugs

bind to receptors to prevent cell signally and block effect

69

Enantiomers can exhibit differences in

absorption
distribution
clearance
potency
toxicity (drug interactions)

70

the therapeutically inactive isomer in a racemic mixture should be regarded as

an impurity

71

efficacy

the ability of a drug to produce the desired therapeutic effect

72

potency

the relationship between the therapeutic effect of a drug and the dose necessary to achieve that effect

73

Increased affinity of a drug for its receptor

makes the drug more potent?

74

Therapeutic index of a drug

ratio of LD50 to ED50

75

commonly measured pharmacokinetic parameters of injected drugs are

elimination half time
bioavailability
clearance
volume of distribution

76

LUNG uptakes

basic lipophilic drugs

77

elimination half time and elimination half life are not equal when

the decrease in the drug's plasma concentration does not parallel its elimination from the body

78

context sensitive half time considers

the combined effects of distribution and metabolism as well as duration of continuous IV administration on drug pharmokinetics

79

rate limiting step of transdermal administration =

diffusion across the stratum corneum of the epidermis

80

Hoffman elimination / ester hydrolysis are responsible for the elimination of (4)

Succhs
atracurium
cisatricurium
mivacurium

81

metabolism is defined as

biotransformation to convert pharmacologically active, lipid soluble drugs into water soluble and often inactive drugs

82

increased water solubility of a drug reduces its

volume of distribution !

bc water soluble = ionized = in the plasma

83

fraction of total drug eliminated during first order kinetics is

independent of the plasma concentration of drug.

- attribute of the drug

84

phase I reactions...

increase the drug's polarity and prepare it for phase II

85

phase II reactions...

covalently link the drug or metabolites with a highly polar molecule that renders it more water soluble for subsequent excretion

86

hepatic microsomal enzymes are located

in the hepatic smooth ER

87

CYP-450 involved in

OXIDATION, REDUCTION, and CONJUGATION of a large number drugs

88

non-microsomal enzymes do not undergo

enzyme induction !!

which is why you can't build a tolerance to succhs

89

tachyphylaxis

tolerance that develops acutely with only a few doses of drug

90

non receptor drug action:

ex. chelating drug

91

immunity is present when

hypo-reactivity is due to the presence of antibodies

92

clearance is directly proportional to

blood flow to clearing organ
extraction ratio
drug dose

93

clearance is inversely proportional to

half-life
drug concentration in the central compartment

94

albumin binds to

acidic drugs

95

alpha1-acid-glycoprotein binds to

basic drugs

96

beta globulin binds

basic drugs

97

highly protein bound drugs typically have a slower rate of

metabolization and elimination

98

drugs cleared by zero order kinetics even in therapeutic doses

aspirin, phenytoin, alcohol, warfarin, heparin, theophylline

99

alt. pharmacodynamics

relationship between the effect site concentration and clinical effect

100

alt. pharmokinetics

relationship between drug dose and plasma concentration

101

context sensitive half time increases in parallel with

the length of infusion